History

A 4-month-old 2.90-kg (6.38-lb) sexually intact female Bichon Frise was referred to our veterinary medical teaching hospital because of persistent hemorrhagic discharge from the vulva. The owner had purchased the puppy 35 days ago. Five days after the purchase, the owner reported that the dog began repeatedly licking its vulva and had bloody discharge from the vulva. Also, the vulva was noticeably swollen. A referring veterinarian examined the dog and performed a vaginal cytologic examination, which revealed numerous bacilli and RBCs but no leukocytes. A presumptive diagnosis of vaginitis was made, and amoxicillin was prescribed for 14 days. The hemorrhagic discharge persisted, and the dog was reexamined by the referring veterinarian immediately before referral to our facility. A CBC was performed and revealed an RBC count of 6.88 × 10⁶ cells/ML (reference range, 4.7 × 10⁶ cells/ML to 8.5 × 10⁶ cells/ML), Hct of 46.6% (reference range, 32% to 55%), and hemoglobin concentration of 14.7 g/dL (reference range, 10.3 to 18.0 g/dL).

At the time of admission at our facility (30 days after onset of hemorrhagic discharge from the vulva), the owner reported that urinations and defecations appeared to be normal. The owner had not noticed any changes in water consumption or other behaviors of the dog, and no other animals were in the household. The dog was current with regard to vaccinations and was not receiving any medications at the time of admission. The owner was specifically questioned with regard to whether the dog was receiving or exposed to exogenous estrogens, and the owner stated that the puppy was not receiving any estrogencontaining products and did not have access to exogenous estrogens.

Physical examination revealed that the dog had a rectal temperature of 38.6°C (101.4°F). Respiratory rate and heart rate were within the respective reference ranges. Body condition score was 3 on a scale of 1 to 5. Mucous membranes were pink, capillary refill time was < 2 seconds, and the dog had no clinical signs of pallor, all of which were considered indicative that she was not anemic at the time of admission.^1,2 Results of palpation of the abdomen and lymph nodes were unremarkable.

A small amount of serohemorrhagic discharge was evident at the vulva. Results of cytologic examination of a specimen collected from the cranial portion of the vagina revealed 70% cornified epithelial cells, 30% intermediate cells, moderate amounts of mucus and debris, numerous RBCs, no leukocytes, and no bacteria.

Question

What is the most likely cause of the persistent (30 days' duration) hemorrhagic discharge from the vulva of this female puppy? Please turn the page.

Answer

Despite the age of this female dog (4 months old), follicular cysts were considered to be the most likely cause of the persistent serohemorrhagic discharge described.

Results

Financial restrictions prevented abdominal ultrasonographic examination. Thus, 750 units of human chorionic gonadotropin (hCG) was administered SC as a combination diagnostic test and treatment. There is a high prevalence of cystic follicles in bitches, compared with the prevalence for other hyperestrogenic conditions, and hCG is relatively inexpensive. It was expected that the hCG would eliminate any cystic follicles, which would result in resolution of the condition. The owner was advised to contact the authors if the puppy's condition did not improve within 2 weeks.

Fourteen days later (44 days after onset of the hemorrhagic discharge from the vulva), the dog was reexamined at our facility. The vulva was still enlarged, and a small amount of hemorrhagic discharge emanated from the vulva. Respiratory rate and heart rate were within the respective reference ranges. The mucous membranes were pink, capillary refill time was < 2 seconds, and there was no evidence of pallor, all of which indicated the dog was not anemic. Results of palpation of the abdomen and lymph nodes were unremarkable. Results of vaginal cytologic examination were unchanged from those obtained 14 days previously. The owner was again questioned as to whether the dog was receiving or exposed to exogenous estrogens, and the owner again indicated that the dog was not receiving any estrogencontaining products and did not have access to exogenous estrogens.

Five hundred units of hCG was administered SC. The owner was instructed to contact the authors within 14 days to report any changes.

Fourteen days later (58 days after onset of the discharge from the vulva), the dog was again examined at our facility because of persistence of the hemorrhagic vulvar discharge. Results of physical examination and vaginal cytologic examination were unchanged from those of the previous examinations. The owner consented to additional diagnostic tests.

Ultrasonographic examination of the reproductive tract revealed that the ovaries were of anticipated size for a prepubertal bitch. The right ovary was 6.4 × 12.0 mm, and the left ovary was 4.0 × 11.2 mm (Figure 1). Neither ovary had any evidence of follicles, follicular cysts, or corpora lutea. The uterus did not contain any fluid. Each uterine horn was 8.8 to 9.9 mm in diameter. The uterus retained the usual appearance of layering of the uterine wall, although the wall was slightly thick (Figure 2). This was consistent with the history of hemorrhagic discharge, which was presumed to be secondary to prolonged estrogen exposure. Both adrenal glands were within expected limits (the right adrenal gland was 1.9 × 12.6 mm).

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Transabdominal ultrasonographic views of the right (A) and left (B) ovaries of a 4-month-old sexually intact female Bichon Frise examined because of persistent hemorrhagic discharge from the vulva of 30 days' duration. Follicular cysts or follicles are not evident. Dimensions of the right ovary are 12.0 mm (cursors No. 1) × 6.4 mm (cursors No. 2), and dimensions of the left ovary are 11.2 mm (cursors No. 1) × 4.0 mm (cursors No. 2). Marks on the left side are at intervals of 5 mm.

Citation: Journal of the American Veterinary Medical Association 233, 2; 10.2460/javma.233.2.235

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Transabdominal ultrasonographic view of the uterus of the dog in Figure 1. The diameter of the uterine horns is approximately 8.8 mm (cursors No. 1) to 9.9 mm (cursors No. 2). No fluid is evident in the lumen of the uterus. Typical layering of the uterine wall is evident, and the uterine wall is slightly thick, which is consistent with prolonged estrogen exposure. Marks at the edge of the image are at intervals of 5 mm.

Citation: Journal of the American Veterinary Medical Association 233, 2; 10.2460/javma.233.2.235

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A serum sample was obtained and submitted for determination of progesterone and estrogen concentrations. Progesterone concentration was 0.61 ng/mL (reference range, < 1.00 ng/mL for a bitch in anestrus or early proestrus), and estradiol-17B concentration was > 500 pg/mL (reference range, < 15 pg/mL for a bitch with no follicular activity and 15 to 50 pg/mL for a bitch with normal follicular activity, respectively).

The owner was again questioned regarding exogenous sources of estrogen for the dog. At this time, the owner acknowledged use of a topical estrogen cream, which she applied on her arms. The owner also indicated the dog would frequently lick her arms after application of the cream. On the basis of this information, no additional treatments were instituted for the dog. The owner was advised to change the location on which she applied the estrogen cream to prevent the dog from estrogen exposure through licking.

Discussion

Exogenous estrogens may induce hyperestrogenism in bitches. To our knowledge, exogenous estrogens affect bitches by causing a condition similar to, but definitely distinct from, persistent proestrus or estrus, with minimal leukocytosis and increased cornified epithelial cells evident during vaginal cytologic examination, possible suppression of RBCs, endometrial diapedesis, and an enlarged vulva.

Hyperestrogenism is usually detected in sexually intact female dogs and is often associated with follicular cysts.³ Administration of hCG without improvement in the clinical condition, as well as evidence of a normal reproductive tract during ultrasonographic examination, eliminates a diagnosis of ovarian lesions.^4,5 Follicular cysts develop from graafian follicles and can be found in 1 or both ovaries. Such cysts would be consistent with clinical signs of prolonged estrus with serohemorrhagic discharge from the vulva and infertility.^5,6 Ultrasonographically, cysts appear as focal hypoechoic to anechoic structures that may have distal enhancement.^4,5 Results of vaginal cytologic examination may include cornified vaginal epithelial cells (which is indicative of estrogenic influence), cellular debris, RBCs, few polymorphonuclear neutrophilic leukocytes, and bacteria.^4,5 Estrogen concentrations of > 20 pg/mL for a prolonged period indicate a source of chronic estrogen production, which is likely to be a follicular cyst or an estrogen-secreting granulosa theca cell tumor.⁵ Sexually intact bitches with an estrogenproducing granulosa theca cell tumor may have signs of a condition similar to, but substantially distinct from, those for proestrus or persistent estrus; vulvar hyperplasia; and mucoid, serosanguineous, or purulent vaginal discharge. Furthermore, bitches with an estrogen-producing granulosa theca cell tumor may be receptive to mating for > 21 days.⁷

Clinical signs of hemorrhagic discharge from the vulva for a prolonged period, an estrogen concentration greater than the reference range, no response to the administration of hCG, a normal reproductive tract on ultrasonographic examination (including no evidence of follicular cysts, follicles, or corpora lutea), and the fact the owner acknowledged application of a topical estrogen cream to her arms and that the puppy frequently licked the owner's arms after application of the cream indicated hyperestrogenism from an exogenous estrogen source.

Estrogens can have a deleterious effect on the hematopoietic system in dogs, and large doses may cause a preliminary leukocytosis followed by leukopenia, hemorrhagic purpura secondary to thrombocytopenia, and anemia.^7,8 Hyperestrogenism apparently blocks the use of erythropoietin by stem cells or causes a decrease in production of extrarenal precursors of erythropoietin.^7,8 Excessive estrogen can cause a condition similar to, but clearly distinct from, prolonged proestrus or estrus, nymphomania, and behavioral changes.⁶ It is characterized by bilateral symmetric alopecia, enlargement of the vulva, and abnormalities of the estrous cycle,^3,8 all of which were consistent with the clinical signs, high estrogen concentration of > 500 pg/mL, ultrasonographic findings of a thickened uterine wall, and hemorrhagic discharge from the vulva for a prolonged period in the bitch puppy reported here.

Outcome

Twenty-one days later (79 days after onset of the hemorrhagic discharge from the vulva), the dog was examined at our facility. The owner reported that she had changed the location on her body to which she applied the topical estrogen cream as well as the time of day at which the cream was applied. The dog reportedly had a good appetite and was energetic at home. Results of physical examination were unremarkable. The vulva was slightly reduced in size but was still larger than would be expected for a prepubertal dog. No hemorrhagic discharge was evident from the vulva. Vaginal cytologic examination revealed 70% cornified epithelial cells, a minimal number of leukocytes, and no RBCs. A serum sample was obtained, and assay results of that sample revealed a decrease in the estradiol-17β concentration to 22.3 pg/mL.